Parathyroidectomy in chronic kidney disease

1.1 Patients with secondary hyperparathyroidism (SHP), with serum PTH level persistently above 800 pg/mL, associated to one or more of the following conditions: 1.1.1 Hypercalcemia and/or hyperphosphatemia refractory to clinical treatment (Evidence). 1.1.3 Extraosseous calcifications (soft tissue and/or cardiovascular) or calcific uremic arteriolopathy (calciphylaxis) (Evidence). 1.1.4 Advanced, progressive and debilitating bone diseases that do not respond to clinical treatment (Evidence). 1.1.5 Presence of enlarged parathyroid glands on ultrasound (volume > 1.0 cm3) (Opinion).

1.1 Patients with secondary hyperparathyroidism (SHP), with serum PTH level persistently above 800 pg/mL, associated to one or more of the following conditions: 1.

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SHP is a frequent complication in CKD patients and it requires monitoring and energetic treatment and prevention measures. In case of clinical treatment failure, PTX is the safe surgical treatment with low complication rates and reduced morbidity and mortality in patients with severe hyperparathyroidism 1-3 .
Imaging methods for locating parathyroid glands are mostly unable to identify all the hyperfunctioning glands 4-6 . Parathyroid ultrasonography and scintigraphy are considered complementary methods, and the difficulty in performing them should not delay surgical treatment, since prepared teams are able to achieve surgical success in most cases 5 . Imaging exams are particularly important in the localization of ectopic glands, which only occur in about 2.5% of patients 5 , or in cases of reoperation due to recurrence or persistence, increasing surgical resolution rates and decreasing complication rates 6 .
In preoperative preparation, aluminum toxicity must be excluded, as this metal is deposited in the bone mineralization front, preventing total bone remodeling that follows PTX. The desferrioxamine (DFO) test has demonstrated high sensitivity and specificity 7 , while bone biopsy is preferred for dubious diagnoses 8 .
Two types of PTX are most commonly performed: subtotal and total with autograft of parathyroid tissue. In subtotal PTX, the surgeon usually elects the smallest gland and/or the one with the best macroscopic appearance as the remaining gland, leaving it whole or performing its partial resection, which is usually identified with non-resorbable sutures to facilitate reinterventions in case of recurrence. In total PTX with autograft, all four glands are removed and a part of the gland with best macroscopic appearance is sectioned and grafted onto a muscle bed, with the most common sites being the forearm and presternal region [9][10][11][12] .
Studies show that both techniques are effective in controlling HPT. The decision between techniques should take into account clinical and surgical aspects, such as degree of alteration of the parathyroid glands, kidney transplantation possibilities, among others 9-14 . The advantages of subtotal PTX are lower rate of severe hypoparathyroidism soon after surgery, since the remaining gland has immediate function, in addition to less need for postoperative calcium and calcitriol replacement. However, studies have observed a higher recurrence rate of HPT, and the re-exploration is more related to surgical complications and morbidities 9 .
Total PTX with autograft shows as advantages total removal of all glands from the neck and lower recurrence rate. The latter, when it occurs, is most often due to hyperplasia in the graft topography, and its surgical re-exploration is simpler and with fewer complications. The disadvantages of this technique are the high rate of postoperative hypoparathyroidism and the time lability related to graft functioning, requiring replacement of larger amounts of calcium and calcitriol in the postoperative period 10 .
Intraoperative PTH dosing aims to confirm removal of all hyperfunctional parathyroid glands (total PTX with autograft) or adequate reduction of the hyperfunctional mass (subtotal PTX,) which is possible due to the short half-life of intact PTH [15][16] . A 70% or greater decrease among values, collected at baseline and after removal of the glands, predicts surgical success in most patients, with good correlation to long-term PTH values 16 . Although efficient, it can increase the surgical time and rarely has the ability to change the surgical approach, besides being scarcely available in Brazil 5 . A useful alternative is PTH measurement in the first days after PTX, since still elevated PTH levels assume the existence of significant residual parathyroid tissue 16 .
Intraoperative freezing is the best technique to confirm whether all removed tissues are indeed of parathyroid origin. If not available, the operation could be extended with partial thyroidectomy and thymectomy, if it is suspected that a gland has not been found 17 .
The auxiliary technique for cryopreservation of parathyroid tissue, for possible future use in cases of definite hypoparathyroidism, was more commonly employed in the past with variable success rates. It demands technical infrastructure with tissue bank requirements 18 . For this reason, and since it is necessary in a minority of patients, its execution has been discontinued in most centers in Brazil 5 .
After successful PTX, there follows a period known as "hungry bone syndrome", which usually occurs in the first days of postoperative period, but that could also start late, and last up to months. The main characteristics of this phase are hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase 10,[19][20][21] . An elevated preoperative alkaline phosphatase is the main predictor of more pronounced hypocalcemia in "hungry bone" 19 . At this stage, a major Ca, oral and intravenous, and oral calcitriol replacement is required, and should be started within the first few hours after PTX. It is important to note the risk of phlebitis and necrosis, if extravasation of the solution occurs when administered into a peripheral vein, and reports of hyperchloremic acidosis, with the use of calcium chloride 21 .
During the "hungry bone" period, it is necessary to pay close attention to serum potassium dosages, as a significant percentage of these patients develop hyperkalemia in the immediate postoperative period, including the need for emergency dialysis. The cause of post-PTX hyperkalemia is controversial, and may be attributed to massive osteoclasts apoptosis and electrolyte balance. Hypocalcemia, resulting from the abrupt reduction in PTH, promotes the influx of sodium (Na) into skeletal muscle cells via a Na-Ca exchange mechanism in the membrane. Then, the entry of intracellular sodium activates the Na/K-ATPase pump, which promotes the efflux of potassium. Preoperative potassium greater than 4.4 mEq/L is a predictor of hyperkalemia in the immediate postoperative period 22 . Dialysis patients are recommended to undergo dialysis in the 24 hours prior to PTX, in addition to dietary potassium restriction in the preoperative period.
Some patients, especially those with pre-dialysis CKD or transplant recipients, develop hypomagnesemia, which often aggravates sustained hypocalcemia in the postoperative period. Correction of hypomagnesemia is followed by improvement in hypocalcemia. Magnesium replacement is done with intravenous magnesium sulfate or oral magnesium salts until levels return to normal 23 .
The hypophosphatemia that follows PTX is due to the deposition of calcium-associated phosphorus in the matrix mineralization during the process of bone formation. Intravenous phosphorus replacement should be avoided, since it leads to precipitation with calcium. Exception made in the case of severe, symptomatic hypophosphatemia, in which the serum P level is below 1.0 mg/dL 24 .
In kidney transplant patients, the renal function after PTX may remain stable or be altered, transiently or permanently [25][26][27][28] . The cause has not yet been fully clarified and it also occurs in patients with primary HPT 26 , possibly related to the hemodynamic effect of calcium and PTH on renal vasculature 27 . Previous tubular lesions and higher PTH values may be related to worsened GFR after PTX 28 . However, it is clear that persistent post-transplant HPT deteriorates graft function and increases the risk of graft loss 29 , besides the worsening of bone mass and possible implication in the progression of calcification. PTX performed prior to renal transplantation shows better results than if it is performed after it, minimizing the hypercalcemia that sets in after the transplant, resulting from persistent HPT 29 .
After hospital discharge, frequent monitoring of bone metabolism-related biochemical and hormonal parameters is essential to guide dosage adjustments for oral Ca and calcitriol. The need to switch from oral Ca as supplement to its binder function, or even an association of both, should always be considered, in the event of hyperphosphatemia, which should include dietary restriction, use of Ca-free binders if necessary, and readjustment of dialysis dose in parallel. This monitoring aims to prevent recurrence, to act early in case of persistent SHP or even hypoparathyroidism and its consequences 1,30 . We consider as therapeutic success of surgical treatment when PTH values are reduced to the target range in dialysis patients (2 to 9 times the reference value of the method) 1 and there is normalization of calcemia in transplant patients with a reduction of PTH > 50% of the baseline value 11 . For kidney transplant patients, the optimal PTH range is variable, and the glomerular filtration rate should always be considered.